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    The Stability of Armature Wire to Maintain the Y-Shaped Chest Tube Curvature at Physiologic Temperature
    (2017-03-14) Olivencia-Yurvati, Albert; Gnasigamany, Jason
    Background: The Y-shaped chest tube with split ends divides within the thoracic cavity, permitting both mediastinal and pleural placement with a single exit port. To maintain the curvature of the pleural tube, we have employed the Jack Richeson 1/16” armature wire. This study tests the migration of the pleural tube due to the expansion of the armature wire at physiologic temperature. The purpose of this study is to provide insight into determining the appropriate biomaterial for the novel Y-shaped chest tube. Methods: This study contains separate experiments for five luminal sizes (20, 24, 28, 32, and 36Fr) of silicone catheter tubes, each wrapped with armature wire. A heated water bath was created with a Cole Parmer Immersion Circulator heater. Tubes were placed in the bath for 24 hours to test the angle changes at the proximal split point and the distal pleural end. Two sets of data were collected for each size, physiologic temperature (n=5) and room temperature (n=5). Results: The tube displacement was measured at proximal and distal sites. Values are compared by ANOVA. Proximal measurements: There is no significant difference in displacement between room and physiologic temperatures (P=0.095). Using the Newman-Keuls method of pairwise multiple comparison, the difference in mean values among the different luminal diameters were noted (within 23.33°C: 32Fr vs. 24 Fr P=0.004; within 37°C: 32Fr vs. 20Fr P=0.012, 32Fr vs. 24Fr P=0.018, 32Fr vs. 28Fr P=0.015, 32Fr vs. 36Fr P=0.028; within both temperatures: 32Fr vs. 20Fr P=0.007, 32Fr vs. 24Fr PDistal measurements: There is no significant difference in displacement between room and physiologic temperatures (P=0.423). There is no significant difference in displacement among the different tube diameters (P=0.073). The effect of different levels of temperature does not depend on which tube luminal diameter is present (P=0.593). Conclusions: These data suggest that change in temperature will not significantly affect the wire to cause tube migration. However, it is noticed that the tube diameter has a significant effect on its migration. Thus, further studies need to be completed to determine the extent of this effect.
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    L-sulforaphane Decreased Contractile Response in Mesenteric Arteries in A Rat Model of Gestational Hypertension
    (2017-03-14) Osikoya, Oluwatobiloba; Goulopoulou, Styliani PhD; Cushen, Spencer
    Background: Maternal hypertension is a state of inflammation characterized by oxidative stress. Exposure of pregnant rats to the Toll-like Receptor 9 activator, ODN2395, induces hypertension and upregulates vascular oxidative stress. The transcription factor, Nuclear Factor Erythroid 2 Like 2 (Nrf2), is a regulator of antioxidant response, is overexpressed in placentas from patients with preeclampsia. However, the role of Nrf2 in maternal vascular dysfunction is unknown. Hypothesis: L-sulforaphane, an Nrf2 activator, will have anti-contractile effects on arteries from pregnant rats treated with CpG oligonucleotides (a model of gestational hypertension). Methods: Pregnant Sprague-Dawley rats were treated with synthetic unmethylated CpG oligonucleotides (ODN2395, 100µg/intraperitoneal injection) or saline (Control) on gestational day 14, 16, and 18 (term=21-22 days). Blood pressure was measured before pregnancy and on gestational day 19 using the tail cuff method. The contractile responses of mesenteric resistance arteries to a thromboxane A2 (TxA2) mimetic, U46619, in the presence or absence of Nrf2 activator, L-sulforaphane (L-S, 40 µM), were assessed by wire myography on gestational day 21. Results: Rats treated with ODN2395 had greater systolic blood pressure on gestational day 19 compared to control rats (Control, n=9: 100±4 mmHg vs. ODN2395, n=7: 119±4 mmHg, p=0.007). Three-hour but not one-hour incubation with L-sulforaphane reduced the contractile response to U46619 in mesenteric arteries from both ODN2395 and control rats (Peak contraction as %Max KCl (120mM), Control Veh: 120.5%±4.85; Control L-S: 39.1%±7.16; ODN2395 Veh: 111.1%±4.19; ODN2395 L-S: 42.6%±2.68). Conclusions: Pregnancy is a state of oxidative stress and this may explain the anti-contractile effects of L-sulforaphane in arteries from normal, healthy rats. In preeclampsia, levels of oxidative stress are greater compared to normotensive pregnancies and thus, systemic treatment with L-sulforaphane or other Nrf2 activators may improve poor cardiovascular outcomes in pregnancies with preeclampsia.
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    Effectiveness and safety of indomethacin for decreasing chest tube duration after coronary artery bypass graft surgery
    (2017-03-14) Gibson, Caitlin PharmD BCPS; Howard, Meredith PharmD BCPS; Hall, Brenton
    Purpose: Early removal of chest tubes in coronary artery bypass graft (CABG) patients is a factor that positively affects length of hospital stay. Indomethacin is sometimes used in one community hospital to reduce chest tube output via reduction in inflammation in an attempt to shorten chest tube duration. Nonsteroidal anti-inflammatory drugs, including indomethacin, are contraindicated in the setting of CABG due to a boxed warning regarding increased risk of cardiovascular thrombotic events. The aim of this study was to determine if the use of indomethacin in CABG patients is safe and effective in shortening the duration of chest tube placement. Methods: This was a retrospective chart review of patients in a 348 bed community hospital receiving indomethacin therapy after CABG surgery. The records of all adult patients receiving CABG surgery between 2010 and 2015 were systematically screened for receipt of at least one dose of indomethacin while chest tubes remained inserted. Charts with admit diagnoses of cardiac arrest or stroke were omitted from review. Identified subjects were individually matched based on demographics, medical history, and concomitant cardiac surgeries. Data collected included patient comorbidities, daily chest tube output, duration of chest tube placement, and concomitant medications. The primary outcome measure was change in time from first dose of indomethacin until removal of chest tubes compared with duration of insertion of chest tubes in control patients. The secondary outcome measure was total duration of chest tube insertion. Safety endpoints included occurrence of thrombotic events, TIMI bleeding in the setting of CABG, or death. Descriptive statistics were utilized. This study was approved by the institutional review board. Results: Sixteen patients received indomethacin and were eligible for inclusion. They were matched 1:1 to 16 patients not receiving indomethacin. Two of the patients in the indomethacin group received heart valve replacement at time of CABG and were able to be matched only on sex and type of valve replaced. The median age was 55 years in the indomethacin group and 56 years in the control group. Twenty-four subjects were male. Indomethacin was associated with a shorter duration of chest tube insertion when comparing time from first dose of indomethacin to chest tube discontinuation with duration of insertion in control. The median decrease in duration of chest tube insertion in the indomethacin group was 14.5 hours. The median total duration of chest tube insertion in indomethacin and control patients was 214.3 and 91.2 hours, respectively. No patients experienced thrombotic events, bleeding, or death during admission. Conclusions: Indomethacin decreased chest tube insertion times, however the clinical impact of this reduction is uncertain. Although it has shown to be safe in this cohort study, more studies are needed to determine if indomethacin has a place in the setting of CABG surgery.
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    Pressor Responses to Voluntary Breathhold is Exaggerated in African Americans with Sleep Apnea and With Hypertension
    (2017-03-14) Osho, Ruth MS; Jouett, Noah; Smith, Michael PhD; Jackson, Hillary MS
    Introduction: Previously, we demonstrated that the chemo-reflex control of sympathetic nerve activity (SNA) is exaggerated in patients with obstructive sleep apnea (OSA), in that the SNA and systolic arterial pressure (SAP) response to a voluntary breath hold was greater than in individuals without OSA. This previous study did not distinguish ethnic differences, nor was the response in hypertensive patients assessed systematically. In this pilot study, we hypothesized that the SAP response to apnea (as an index of the chemo-reflex sensitivity), is exaggerated in African-Americans (AA) with OSA compared to healthy AA individuals, and that the presence of hypertension exacerbated this response. Methods: Standard auscultatory blood pressure was measured in triplicate during quiet rest and immediately following a 20 sec voluntary end-expiratory breath hold (apnea) in the following groups of AA volunteers: 18 normotensive (7 with OSA) and 28 hypertensive (16 with OSA). Results: Post-apnea change in SAP increased significantly more in patients with OSA than those without OSA, p Conclusions: These data demonstrate that measurement of the SAP response to a voluntary breath hold can distinguish AA subjects with OSA from those without OSA, and that the presence of hypertension may exaggerate these responses.
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    Comparison of Time to Tissue Plasminogen Activator in Patients Receiving In-Hospital Vs. Emergency Medical Services Lab Draws
    (2017-03-14) Hulsizer, Abigail; Gibson, Pharm.D, Caitlin; Gandhi, Hiral
    Purpose: Tissue plasminogen activator (tPA) is beneficial when given within 4.5 hours of acute ischemic stroke onset, giving patients an increased likelihood to recover without any significant disability within a 3-month time period. Delays in diagnosis and laboratory data can place patients outside the tPA window. In an attempt to shorten time to tPA administration, some emergency medical services (EMS) companies have begun drawing blood for labs in the ambulance. The aim of this study is to determine if laboratory draws inside the ambulance shorten the time to tPA administration. Methods: This study is a retrospective chart review of patients admitted to a 348-bed community hospital for acute ischemic stroke who received tPA. Patients were included if they were greater than 18 years of age who have arrived at the hospital via EMS who have had an ischemic stroke with a clearly defined time of onset, a deficit measurable on the NIHSS, and a baseline computed tomographic (CT) scan of the brain that showed no evidence intracranial hemorrhage. Patients were excluded if they arrived with rapidly improving symptoms signaling a TIA, if they did not have a definitive ischemic stroke diagnosis, and/or if they had the stoke on site and did not have the opportunity to have an EMS vehicle transport. The primary outcome was to determine if receiving labs in the EMS significantly reduced door to needle time compared to receiving labs in the Emergency Department (ED). The secondary outcome was to determine if there were better health outcomes, as determined by discharge NIH scores, in patients receiving tPA within a shorter amount of time due to getting labs in an ambulance. Safety outcomes were adverse events related to tPA, such as angioedema, intracranial hemorrhage and anaphylaxis within 24 hours. Descriptive statistics were utilized. Results: Twenty-nine patients met inclusion criteria with one patient making two visits in the past year. The mean age and door to needle time (DTN) were 58.8 years-old and 77.5 minutes respectively. Hypertension, diabetes and smoking history were present in 78.1 percent, 43.7 percent, and 30 percent of patients, respectively. Of those who came by ambulance only 30 percent (n=11) had labs drawn in route to the hospital. The average DTN for those who had labs drawn in the EMS was 77.7 minutes. From the remaining patients, the average DTN time from the who had labs drawn at the hospital was 86.3 minutes. During the study, two patients expired from complications of tPA. One patient suffered a repeat stroke within the year. Conclusions: EMS lab draw in patients suspected of acute ischemic stroke was associated with a 8.6-minute decrease in door to needle time compared to patients who had labs drawn at the hospital. Clinical significance is likely negligible.
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    Effects of Acute Intermittent Hypoxia Training on Markers of Cardiac Autonomic Regulation
    (2017-03-14) Griffin, Brandon; Cooley, Daniel; Jouett, Noah; Smith, Michael; Bysani, Kaethan
    Background and Hypothesis: The intermittent episodes of hypoxia observed during apneic events of obstructive sleep apnea (OSA) increase the risk of cardiovascular disease, by altering sympathetic nervous activity (SNA); increased SNA outflow is postulated to be mediated by activation of angiotensin II receptors. Hypoxic apneic episodes were used to simulate short-term OSA with an intermittent hypoxic training (IHT) protocol, while assessing several indices of autonomic control with or without treatment with angiotensin receptor blockers (ARBs). Our hypotheses were: 1)Acute IHT training in healthy patient will increase indices of sympathetic control post-IHT compared to baseline, and 2)blockade of angiotensin II receptors with ARBs will attenuate the change in autonomic control associated with IHT. Materials and Methods: Eight healthy subjects were studied on two days. On day 1, subjects were treated with placebo or Losartan and IHT. On Day 2, the study was repeated with the alternative treatment (ARB or placebo). The IHT protocol consisted of a 5 minute baseline, then 3 breaths of nitrogen followed by 20 second expiratory apneas with a 40 second recovery period between each apnea for a total of 20 apneas, and then followed by a 5 minute post-IHT period. Heart rate (ECG), beat-to-beat blood pressure (Finometer), and O2 saturation (pulse oximeter) recorded continuously. The following autonomic indices were derived from these measures RRI, pNN50, and HF-RRI as indices of parasympathetic control, and LF-MAP, LF-SAP, and LF-RRI as indices of sympathetic control. Results: The IHT conditioning produced significant reductions in parasympathetic control (evidenced by RRI, pNN50 and HF-RRI, p0.05) and increases in sympathetic control (evidenced by LF-MAP, LF-SAP and LF-RRI, p0.05). Treatment with the ARB did not significantly alter the responses of any of these variables (although the a levels for sympathetic indices were near significance ~0.1-0.15). Conclusions: Acute IHT training in healthy individuals significantly enhanced the indices of sympathetic control, and reduced the indices of parasympathetic control. The ARB treatment did not significantly affect these measures although the sympathetic measures trended toward significance. Coupled with our prior finding that ARBs reduced the SNA post-IHT, these data suggest that further investigation is needed that includes a larger subject number and longer stimulus period similar to actual OSA.
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    Circulating Cell-free Mitochondrial DNA In Normal Human Pregnancy and In Experimental Preeclampsia
    (2017-03-14) Phillips, Nicole; Sprouse, Marc; Jarvis, Sara; Okada, Yoshiyuki; Morton, Jude; Davidge, Sandra; Fu, Qi; Goulopoulou, Styliani; Chaudhari, Sarika
    Background: Mitochondrial DNA (mtDNA) is a damage-associated molecular pattern (DAMP) with potent immunogenic and inflammatory properties. Circulating cell-free mtDNA is increased in various inflammatory conditions associated with intense cell apoptotic processes. Pregnancy is characterized by systemic inflammation and placental apoptosis, which increase with advancing gestational age. The temporal changes of cell-free mtDNA during healthy pregnancy and in pregnancies with preeclampsia are unknown. Hypothesis: Circulating cell free mtDNA increases with gestational age in pregnant women and these changes positively correlate with maternal cardiovascular responses and neonatal biometrics. In a rat model of preeclampsia, circulating mtDNA is increased compared to normotensive control rats. Methods: Normal Human Pregnancy: Maternal blood samples were collected at early pregnancy (≤ 8 weeks of gestation), late pregnancy (32-36 weeks), and postpartum (6-10 weeks after delivery) in healthy, normotensive, pregnant women (n=21). Experimental Model of Preeclampsia: Reduced uterine perfusion pressure (RUPP) was surgically induced in pregnant rats on gestational day (GD) 14. Maternal blood samples were collected from RUPP rats (n=11) and control rats (Sham, n=11) on GD20. Absolute real-time PCR quantification of mtDNA was performed on whole genomic extracts from maternal human and rat sera using TaqMan® probes and chemistry. Results: Normal Human Pregnancy: Circulating mtDNA in late pregnancy were greater compared to early pregnancy (0.02 ± 1.2 pg/μL vs. 0.04 ± 1.2 pg/μL, p=0.04) and remained elevated post-partum (0.03 ± 1.2 pg/μL). Both blood pressure and heart rate increased from early to late pregnancy and decreased postpartum (pExperimental Model of Preeclampsia: RUPP rats had increased circulating mtDNA as compared to the sham group (0.30 ± 0.04 copy number/µL vs. 0.18 ± 0.04 copy number/µL, p=0.03). Conclusions: In normal pregnant women, circulating mtDNA change with advancing gestational age and may reflect rates of placental cell apoptosis. In a rat model of preeclampsia associated with placental ischemia, circulating cell free mtDNA is elevated in late pregnancy. The temporal changes in mtDNA in preeclampsia and their functional role in normal and preeclamptic pregnancies need to be further evaluated.
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    Magnetic Resonance Angiography to Assess Anomalous Coronary Arteries in Children at 3-Tesla: Diagnosis, Risk Stratification, and Interobserver Reliability.
    (2017-03-14) Hamby, Tyler; Muyskens, Steve; Olmstead, Keegan
    Background: Anomalous aortic origin of the coronary arteries (AAOCA) is the second most common cause of sudden cardiac death (SCD) in young athletes. The prevalence, pathophysiology, and optimal method of evaluating AAOCA are unknown. The reliability of coronary magnetic resonance angiography (MRA) in assessing AAOCA, and the use of contrast enhanced coronary MRA in children at 3-Tesla has not been well described. We present our institutional experience using a 3-dimensional (3D) IR-FLASH sequence with slow gadolinium infusion and respiratory navigation at 3-Tesla to diagnose and risk stratify AAOCA in children. Methods: A retrospective review was conducted of all MRA patients referred for possible AAOCA between January 1, 2011 and May 9, 2016. Patients with complex congenital heart disease were excluded. Coronary anomalies with an intramural or interarterial course were classified as high risk, and a high aortic origin or intraseptal course were classified as low risk. Completed studies were anonymized and evaluated by two blinded independent observers for image quality, diagnosis of AAOCA, intramural course, and interarterial course. Reliability analyses, utilizing kappa, assessed diagnostic agreement between raters. MRA and surgical findings were compared in patients with AAOCA repair. Results: Fifty-nine patients were referred for suspected AAOCA (median age 13.79 years, range 5.19 – 19.84, 73% male). For 58 successfully acquired angiograms, 31 were high risk, 11 were low risk, and 16 were normal. Overall image quality was rated good to excellent. The two raters showed excellent agreement on image quality, κ = .85 (93%), diagnosis of AAOCA, κ = .81 (91%), and diagnosis of proximal interarterial course, κ = .81 (88%). There was moderate agreement about diagnosis of intramural course, κ = .63 (74%). For all 11 cases with surgical repair, the combined MRA ratings correctly diagnosed the presence of AAOCA and interarterial course. The presence of an intramural course was correctly rated in all 9 cases, while the absence of an intramural course was correctly rated in 1 of 2 cases. Conclusions: Coronary MRA using 3D IR-FLASH with slow contrast infusion at 3-Tesla showed high inter-rater reliability for diagnosing and characterizing AAOCA in pediatrics. Furthermore, findings were validated at time of surgical repair. This protocol is an effective means to examine AAOCA in pediatric patients and help stratify those who may be at high risk of SCD.
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    Exposure to Synthetic CpG DNA During Pregnancy Increases Expression and Activity of Cyclooxygenase in Maternal Arteries
    (2017-03-14) Osikoya, Deborah; Jaini, Paresh; Nguyen, An; Valdes, Melissa; Goulopoulou, Styliani; Dimos, Bradford
    Objective: Preeclampsia is a pregnancy-associated disorder that is characterized by elevated maternal blood pressure, end organ damage, and/or proteinuria. This pregnancy syndrome affects 2-8% of pregnancies worldwide and has no treatment other than fetal delivery. The mechanisms behind the development of this condition remain unknown and is one of the barriers preventing the development of effective treatment. One of the suggested etiologies behind preeclampsia is activation of the innate immune system. We have previously determined that maternal exposure to CpG DNA (a ligand of Toll-like Receptor-9, TLR-9) causes maternal hypertension and excess vasoconstriction. In cancer cells, CpG DNA/TLR-9 activation leads to upregulation of cyclooxygenase (COX), which is the rate-limiting step in the conversion of arachidonic acid to prostaglandins and thromboxanes. It is unknown whether treatment with CpG DNA during pregnancy affects COX in maternal and fetal tissues. Hypothesis: Treatment of pregnant rats with CpG DNA induces maternal hypertension and increases COX function in maternal and fetal tissues. Methods: Pregnant Sprague-Dawley rats were treated with ODN 2395 (synthetic CpG DNA, 100μg/rat/ i.p. injection) and saline (control group) on gestational days (GD): 14, 16, 18 (term: 21-22 days). Tail cuff blood pressure was measured on GD19. On GD20, rats were euthanatized and maternal liver and arteries as well as fetal tissues were frozen for western blot analysis. Thromboxane B2 (TxB2) was measured in serum and media from maternal arteries by ELISA. Results: ODN 2395 increased systolic BP (Control: 100±4 mmHg vs. ODN2395 119±4 mmHg, p=0.006). Serum TxB2 was greater in the ODN 2395 group compared to control rats (Control: 65.2±8.9 ng/mL vs. ODN2395: 123.6±19.7 ng/mL, p=0.03). ODN2395 also increased release of TxB2 from mesenteric (Control: 28.2±4.3 pg/mg tissue vs ODN 54.5±6.2 pg/mg tissue, p=0.008) but not from uterine arteries (p>0.05). Western Blot analysis revealed greater expression of COX-2 in mesenteric (p=0.002) and uterine arteries (p=0.006) in ODN2395-treated animals. ODN2395 increased COX-1 expression in mesenteric arteries (p=0.006) and showed a moderate effect on uterine arteries (p=0.07). No differences were observed between treatment groups for COX-1 and COX-2 in maternal (p>0.07) and fetal liver (p>0.20). Conclusions: Exposure to CpG DNA during pregnancy induced maternal hypertension and augmented function of COX in maternal arteries.
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    Exaggerated Pressor Response to Voluntary Apneas in Patients with a History of Anxiety
    (2017-03-14) Jouett, Noah; Winter, Scott; Lopez, Karla; Gill, Jaskirit; Adams, Kathryn; Grimwood, Brian; Franks, Susan; Burton, Mandy; Smith, Michael; Griffin, Brandon
    Background and Hypothesis: Patients with anxiety disorders tend to have an increased risk of cardiovascular complications including heart failure,cardiovascular mortality, and coronary heart disease. Knowing that an increase in sympathetic activity is detrimental to cardiovascular health this study was conducted to test the hypothesis that anxiety patients would demonstrate increased sympathetic responses to a voluntary apnea, a recognized physiologic stress that simulates the typical stress response. Methods: Previously, our laboratory has shown that systolic arterial pressure (SAP) changes are a reliable index of sympathetic responses during voluntary apneas. Therefore, we studied the SAP responses to voluntary apneas in 10 patients diagnosed with generalized anxiety disorder and 37 healthy control subjects. Room air voluntary apneas were performed by each subject six times while SAP (Finometer and auscultatory) and heart rate (ECG) responses were measured continuously during each apneic episode. Peak changes in arterial pressure from baseline to end of apnea were quantified. Results: The pressor responses to voluntary apneas in the anxiety patients exhibited a marked increase in SAP (16.962 ± 8.002, P Conclusions: These data demonstrate that anxiety subjects have enhanced sympathetic neural activity responses (as measured by the pressor response) to a mild physiologic stressor that does not provoke a response in non-anxious individuals. These data may explain, in part, the increased cardiovascular complications seen is this population, and suggest that the pressor response to apnea may be a simple tool for assessing altered physiologic function and cardiovascular risk in these patient populations.
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    Mid- And Long-Term Follow Up Of Repeat Right Ventricular Outflow Tract Reconstruction Using The Medtronic Freestyle Porcine Aortic Root
    (2017-03-14) Hamby, Tyler; Munawar, Maham; Kuo, James
    Purpose: A stentless porcine aortic root bioprosthesis has been primarily used at Cook Children’s Medical Center (CCMC) for right ventricular outflow tract (RVOT) reconstruction. The purpose of this research was to quantify longevity of the Medtronic Freestyle Porcine Aortic Root and the predictors of its longevity. Methods: A retrospective chart review was conducted of all RVOT reconstructions using porcine aortic root at CCMC between 2002 and 2015. Patients who had a Ross procedure or who were lost to follow up within one year were excluded. For each patient, gender, age, weight, body surface area (BSA), and valve size were abstracted from medical charts. Additionally, survival and reintervention data were captured. Overall freedom from earlier reintervention was assessed using the Kaplan-Meier method. Predictors of longevity were examined with Cox regression. Results: There were 194 operations performed on 188 patients. Excluding patients with Ross procedures, those lost to follow up, and three patients who had died from unrelated causes, 163 patients were examined. Thirty-eight patients (23.3%) required earlier reintervention. The 5-year freedom from reintervention rate was 93.2% (95% CI 86.7-96.6%), and the 10-year rate was substantially lower at 48.4% (95% CI 34.9-60.6%). Regression analyses revealed that age years, weight kg, BSA Conclusions: These data suggest that younger and smaller patients are significantly more likely to require earlier reintervention, but sex is not affiliated with need for earlier reintervention. Upon comparison to other studies, the Freestyle valve’s longevity is comparable to alternative valve replacements.
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    Brief Exposure to Intermittent Hypoxia Prolongs QTc in Human Subjects, which is Abrogated with AT1a Receptor Blockade.
    (2017-03-14) Bysani, Kaethan; Cooley, Daniel; Cutler, Michael; Raven, Peter; Smith, Michael; Jouett, Noah
    Purpose: Patients with Obstructive Sleep Apnea (OSA) frequently succumb to sudden cardiac death (SCD). Prolongation of the QTc, possibly via intermittent hypoxia (IH) mediated activation of angiotensin II type 1a receptors (ATR1a), predisposes towards SCD. Hence, the present study tested the hypothesis that (1) a brief exposure of IH lengthens QTc which (2) is abrogated with Losartan, an antagonist of ATR1a. Further, we evaluated how Losartan affects the relationship between direct measurements of muscle SNA (MSNA) and QTc via linear regression analyses during IH. Methods: Seven healthy human subjects were recruited with normal 12-lead ECGs. Subjects ingested either placebo or 100 mg of Losartan 1 hour prior to experimentation, and then repeated the study on a separate day in a randomized, repeated measures design. 3-lead ECG and MSNA (peroneal microneurography) were recorded throughout the study. Subjects were exposed to 20 minutes of IH, which was composed of 20 cycles of the following: 2-3 breaths of 95-100% N2, 20-second end-expiratory apnea, and 40-second room-air recovery. QTc (determined by Bazett’s formula) averages were compared statistically using a repeated-measures ANOVA. Results: Losartan did not alter baseline QTc (P = 0.17). IH + Placebo significantly prolonged QTc (baseline: 359.8 ± 4.8 ms vs. IH: 368.3 ± 4.8 ms, P 2 = 0.06, IH + Losartan: R2: 0.22). Conclusions: IH prolongs QTc, which is prevented with Losartan . Furthermore, IH alters the relationship of MSNA and QTc, in part through activation of ATR1a. Future studies should evaluate the possible cardioprotective benefits of ATR1a antagonists in OSA patients.
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    Overshoot in Cerebral Perfusion Following Release of Simulated Obstructive Apnea
    (2017-03-14) Liu, Xiaoli; Akinbola, Ebunoluwa; Shi, Xiangrong; White, David III
    Purpose: The purpose of this study was to examine and quantify the hypothesis that there is a surge in cerebral perfusion and arterial pressure, following the release of the modified Mueller maneuver. Methods: Nine healthy men (28 ±1 yr old) performed the Mueller maneuver (attempted inspiration against closed glottis after a forced expiration) and the modified Mueller maneuver (attempted inspiration against closed glottis after a normal expiration) for 15 seconds, respectively, in a random order. The study was approved by the IRB at UNTHSC (Project #2013-121). Heart rate (HR), mean arterial pressure (MAP), cerebral blood flow velocity of the middle cerebral artery (VMCA), arterial oxygen saturation (SaO2) and cerebral tissue oxygen saturation (ScO2) were continuously measured during the maneuvers. Cerebral vascular resistance index (CVRI) was estimated from the ratio of MAP/VMCA. Changes in the hemodynamic parameters were assessed during the first and last 5 seconds of simulated obstructive apnea, respectively, and the first 5 seconds after release of the apnea. Results: Variables were extrapolated to examine percent change from baseline for the first 5 seconds of the maneuver, last 5 seconds of the maneuver, and the release of the maneuver. Neither regular, nor modified, maneuvers elicited significant changes in cardiovascular variables. After the release of the maneuvers, however, both MAP and VMCA were significantly augmented. A significant decrease in CVRI was present after the Mueller maneuver. Conclusions: In conclusion, there is a surge in VMCA associated with an overshoot of MAP following release of simulated obstructive apnea. This sudden increase in cerebral perfusion seems to be driven by an augmented perfusion pressure in the modified Mueller maneuver. This study indicates that obstructive apnea simulated by either regular or modified Mueller maneuvers may lead to instability of cerebral perfusion during the initial phase of resuming breathing.
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    Does Intermittent Hypoxia Training Augment Antioxidant and Anti-Glycation Enzymes in Rat Brain?
    (2017-03-14) Cherry, Brandon; Williams, Arthur Jr.; Marianna, Jung; Myoung-Gwi, Ryou; Mallet, Robert T.; Nguyen, Julian
    Hypothesis: Intermittent hypoxia training (IHT) has been found to minimize damage in the brain of rats subjected to ischemic stroke and alcohol intoxication-withdrawal, but the neuroprotective mechanisms are unclear. The finding that antioxidant treatments during IHT blunt the protection identifies a pivotal role of reactive oxygen species (ROS). Because ROS activate expression of antioxidant and anti-glycation enzymes, this study addressed the hypothesis that IHT augments these enzymes in rat brain. Specifically, the cerebral activities of anti-glycation (glyoxalase-1, i.e. GLO1), anti-oxidant (glucose 6-phosphate dehydrogenase, i.e. G6PDH) and hypoxia-inert (lactate dehydrogenase, i.e. LDH) enzymes were analyzed in IHT and non-hypoxic rats. Material and Methods: Ten rats (5 males) completed a 20 day IHT program (5-8 daily cycles of 5-10 min exposures to 9.5-10% O2 followed by 4 min room air exposures), and another 10 rats (5 males) were sham-conditioned by cyclic exposures to 21% O2. One day after completing the IHT or sham programs, the rats were isoflurane-anesthetized and decapitated. The cerebra were harvested, flash-frozen in liquid N2, pulverized in a mortar under liquid N2, homogenized in phosphate buffer, and centrifuged. Enzyme activities in supernatants were analyzed by spectrophotometry, and total protein content by colorimetric Bradford assay. Results: Activities of GLO1 were 78 ± 8 and 62 ± 7 mU/mg protein in the IHT and sham groups, respectively (P = 0.23). G6PDH activities were 21 ± 2 and 24 ± 2 mU/mg protein in the IHT and sham groups (P = 0.32). As expected, LDH activities were similar in the two groups: 899 ± 49 mU/mg protein in the IHT rats, and 940 ± 58 mU/mg protein in the sham rats (P = 0.60). Thus, IHT did not produce a statistically significant treatment effect on these enzymes. Conclusions: The 20 day IHT program, which exerts robust cerebroprotection against ischemia-reperfusion and ethanol intoxication-withdrawal, did not augment activities of selective antioxidant and anti-glycation enzymes. The impact of IHT on other antioxidant (e.g. glutathione peroxidase, superoxide dismutase, catalase) and anti-glycation (e.g. glyoxalase-2) enzymes remains to be evaluated. It also is possible that IHT activates other cytoprotective mechanisms, including signaling cascades that ameliorate mitochondrial permeability transition, oxidative stress and other mechanisms of neural injury. Such alternative mechanisms merit investigation.
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    Quantification of Nucleus Tractus Solitarius neurons projecting to Hypothalamic Paraventricular Nucleus
    (2017-03-14) Beig, Mirza; Ellazar, Sharon; Mifflin, Steve; Nguyen, Dianna
    Background: Nucleus tractus solitarius (NTS) neurons integrate and relay visceral afferent inputs to various sites in the brain, notably the hypothalamic paraventricular nucleus (PVN). Understanding connectivity between the NTS and PVN will provide insight into possible interactions between the two areas in normal and pathophysiology. Purpose: To quantify the number of NTS neurons that project to the PVN using the retrograde transport agent cholera toxin B (CTB). Methods: Adult male Sprague-Dawley rats (n=3) were anesthetized intraperitoneally with ketamine (75mg/kg) and Dexdomitor (0.5mg/kg) then placed in a stereotaxic frame. Under aseptic conditions, the cranium overlying the PVN was exposed. Using a glass electrode, 100nL of 0.25% CTB in isotonic saline was slowly injected into the PVN bilaterally and the electrode withdrawn after 5 minutes. The skin was sutured and animals were allowed to recover. Three weeks later, the rats were transcardially perfused with 4% paraformaldehyde and their brains were harvested. PVN sections (40um thick) were used to verify the injection site. NTS sections (40um thick) were processed using immunohistochemistry. Polyclonal anti-CTB antibody (1:2000, Millipore) and secondary antibody Cy3 Donkey Anti-Goat (1:800, Jackson ImmunoResaerch Laboratories, Inc.) were used to visualize NTS neurons with axonal projections to PVN. Monoclonal anti-tyrosine hydroxylase (TH) antibody (1:1000, Millipore) and secondary antibody Alexa Fluor 488 Donkey Anti-Mouse (1:800, Jackson ImmunoResearch Laboratories, Inc.) were used to visualize catecholaminergic neurons. The number of CTB-immunoreactive, TH-immunoreactive, and co-labeled CTB and TH neurons were counted manually using Image J. Analysis was restricted to those NTS sections that had CTB-immunoreactivity and ranged from 15-21 sections each in the 3 rats. CTB injection sites were within the boundaries of the PVN. Results: We found 110±6 CTB immunoreactive and 346±33 TH immunoreactive neurons in NTS. 29±5 neurons were dual labeled with CTB and TH immunoreactivity indicating catecholaminergic NTS neurons projected to PVN. Conclusions: The majority of NTS neurons that project to PVN appear to be non-catecholaminergic. Approximately 10% of catecholaminergic NTS neurons project to PVN. Results will be useful in future studies using laser capture microdissection to examine gene expression in NTS neurons that project to PVN under a variety of conditions (e.g., hypoxia, hypertension).
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    Cerebral Blood Flow Changes During Acute Apneic Episodes Simulating Obstructive Sleep Apnea
    (2017-03-14) Bysani, Kaethan; Griffin, Brandon; Jouett, Noah; Smith, Michael; Cooley, Daniel
    Background: Obstructive sleep apnea (OSA) has not only been linked to hypertension and increased cardiovascular risk, but it can also result in mental status changes such as memory impairment. Under normal conditions, autoregulation in the cerebral vasculature maintains a constant flow rate to the brain. As such, the observed changes in the mental status may result from altered cerebral blood flow in OSA patients. By simulating apneic conditions using Intermittent Hypoxic Training (IHT), we can approximate the effect of OSA on cerebral blood flow using a Transcranial Doppler (TCD) to monitor middle cerebral artery (MCA) flow velocity. Using these techniques, we tested the hypothesis that IHT would cause alterations in cerebral blood flow in healthy individuals. Methods: Nine healthy subjects were recruited for the study. Subjects were between 18-40 years of age and free of any pre-existing OSA or Cardiovascular disease. The IHT protocol consisted of a series of hypoxic apneas in which subjects inhaled 2-3 breaths of nitrogen, followed by a 20-second apnea and 40 seconds of room air breathing recovery every minute for 20 minutes. TCD was used to record MCA velocity throughout the study and, additionally, ECG and cardiopulmonary perimeters were also recorded. Results: The MCA velocity during 5 minutes baseline and 5 minutes post-IHT was compared. The measured TCD flow velocity was not statistically different (p [greater than] 0.05) between baseline and post-IHT including the following TCD variables: systolic, diastolic, mean, pulsatility, MAP coherence, MAP phase, MAP transfer and vascular resistance (all p [greater than] 0.05). Conclusions: Cerebral blood flow measures were not significantly altered following IHT in these healthy individuals. The data demonstrates that a 20 minute period of simulated sleep apnea does not affect steady-state cerebral blood flow. Thus, it is likely that cerebral autoregulation is sufficient to maintain normal blood flow in healthy subjects and is not affected by this period of IHT. Further studies may need to examine chronic OSA subjects to discern whether altered cerebral blood flow plays a pathophysiologic role in the disease.
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    For General Health, is Heavy Alcohol Use Related to Heart Disease in Adult Woman Aged 45-64?
    (2017-03-14) Braithwaite, Alycia; Rutledge, Erin; Tannery, Hayley; Hartos, Jessica; Williams, Jamie
    Introduction: Heart disease and general alcohol use are leading health concerns in the general population, but little is known about the relationship between heart disease and heavy alcohol use in women aged 45-64. The purpose of this study was to assess the relationship between heavy alcohol use and heart disease in middle-aged women. Methods: This cross sectional analysis used 2014 BRFSS data for females ages 45-64 from Arkansas, Kentucky, Louisiana, and West Virginia. Multiple logistic regression analysis was used to assess the relationship between lifetime heart disease and heavy alcohol use while controlling for age, ethnicity, marital status, income level, exercise, weight status, diabetes, and tobacco use. Results: A small percentage of female participants aged 45-64 reported lifetime heart disease (6-8%) or heavy alcohol use (2-6%). After controlling for demographic factors, heart disease was not significantly related to heavy alcohol use in any of the four states. However, heart disease was significantly related to exercise in AR, KY, and WV, and significantly related to diabetes in KY and LA. Conclusions: In summary, heart disease was not significantly related to heavy alcohol use but was significantly related to exercise and diabetes in general population samples of women aged 45-64. Although this study was limited by poorly defined variable measurements and a lack of direction of influence, it is recommended that primary care providers screen and educate their middle-aged female patients on the relationship between heart disease, exercise and diabetes. Given low prevalence of heart disease in the target population and lack of significant relationship between heart disease and heavy alcohol use, it is not indicated to screen for heart disease and heavy alcohol use in every middle-aged woman. Screening for either is recommended if the patient presents with symptoms.
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    Uterine perivascular adipose tissue potentiates vasoconstriction in maternal arteries during rat pregnancy
    (2017-03-14) Goulopoulou, Styliani; Osikoya, Oluwatobiloba
    Background: Perivascular adipose tissue (PVAT) functions mostly to increase vasodilation in healthy conditions, but increases vasoconstriction in diseased states. During pregnancy, adipose tissue expands, and uterine arteries (UTA) undergo substantial remodeling. Previously, our laboratory showed that uterine PVAT potentiates contractile responses in UTA from pregnant but not in arteries from non-pregnant rats. It is unknown, however, if the effects of uterine PVAT are vascular bed specific and if they are mediated by pregnancy. Hypothesis: Uterine PVAT potentiates contractions in maternal arteries independently of vascular bed and this pro-contractile property is mediated by pregnancy specific factors. Methods: Sprague-Dawley pregnant rats were sacrificed on gestational day 16 (term=21-22) and aged-matched non-pregnant rats were used as controls. Uterine PVAT, and isolated segments of UTA and mesenteric arteries (MES) mounted onto a wire myograph. To determine whether uterine PVAT has pro-contractile effects independently of vascular bed, pregnant UTA and MES were incubated with uterine PVAT (0.1 g) for 30 minutes. To determine whether the pro-contractile effects of uterine PVAT are mediated by pregnancy specific changes, UTA from pregnant and non-pregnant rats were incubated for 30 minutes with non-pregnant PVAT (0.1 g) and pregnant PVAT (0.1 g), respectively. Concentration response curves to potassium chloride (KCl, 4.7 – 80 mM) were performed in all arteries. Force generated at each KCl concentration was expressed in mN and area under the curve (AUC) was used to quantify total contraction. Results: MES from pregnant rats had increased contractile responses to KCl when incubated with uterine PVAT (AUC, -PVAT: 366±46 vs. +PVAT: 529±53, P = 0.02). UTA from pregnant rats had increased contractile responses to KCl when incubated with uterine PVAT (AUC, -PVAT: 893±40 vs. +PVAT: 1092±59, p=0.004). Preliminary data showed that PVAT from non-pregnant rats increased contractile responses in UTA from pregnant rats (KCl 30 mM, -PVAT: 4.7±0.9 mN vs. +PVAT: 11.4±1.4 mN, p=0.047). Pregnant PVAT had no effect on UTA from non-pregnant rats (p [greater than] 0.05). Conclusions: Uterine perivascular adipose tissue potentiates vasoconstriction in both uterine and mesenteric arteries from pregnant rats. These effects may be due to vascular remodeling during pregnancy.
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    Diastolic Properties in Older Mice: Comparison Between C57Bl6J and C57BL6N.
    (2017-03-14) Taffet, George; Acharya, Deepak; Reddy, Anilkumar; Yechoor, Poornima; Pham, Thuy; Hermosillo, Jesus; Harley, Craig; Knebl, Janice; Karim, Sanaa
    Purpose: Cardiac aging in both humans and mice is associated with diastolic dysfunction, and impairment of the left ventricle filling. Age-related factors contributing to this filling impairment include fibrosis of the ventricle and impaired calcium handling by cardiomyocytes. Most aging studies use the C57Bl6/J (J mouse), but the C57Bl6/N (N mouse) has similar longevity without extensive cardiac fibrosis at comparable ages. Hence, this study is designed to identify the effect of fibrosis on diastolic function. Methods: We performed Doppler and 2-D echocardiography on fourteen 29 months old C57B16 (J and N’s) mice under 1% Isoflurane. The parameterized diastolic filling (PDF) formalism was used to comprehensively evaluate the diastolic dysfunction modeling the ventricle as a damped spring with spring stiffness (k), damping constant (c), initial stretch (x0). Small doses of Ivabradine were given to control heart rate for this assessment. Results: The N mice showed a c value of 205 ± 15, k of 7940 ± 530 and a xo of -.23 ± .004 in comparison to the J mice that showed a c value of 195 ± 14, a k value of 10,420 ± 800 and a xo value of -.016 ± .001. Conclusions: Though systolic function was preserved in old N’s and J’s, the spring stiffness (k) was significantly higher for the old J’s. This suggests fibrosis stiffens the old heart dramatically, but the larger LV diameter in the N’s suggests that fibrosis may prevent chamber enlargement with aging.
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    Combined Effects of Remote Ischemic Preconditioning and Aerobic Exercise on Sympathetic Responses: A Novel Adaptation of Blood Flow Restriction Exercise
    (2017-03-14) Colby, Hannah; Rickards, Caroline; Sprick, Justin
    Purpose: Remote ischemic preconditioning (RIPC) is an innovative therapy used to attenuate tissue damage sustained by ischemia-reperfusion injury. Blood flow restriction exercise (BFRE) is a training method that also limits blood flow to the active muscles during exercise. We implemented a novel approach to BFRE with cyclical bouts of blood flow restriction and reperfusion, reflecting the RIPC model, which could elicit similar protection against ischemia-reperfusion injury. A concern about the use of BFRE, however, is the potential amplification of the exercise pressor reflex, which could be unsafe in at-risk populations. We hypothesized that cyclical BFRE would elicit a greater increase in sympathetic outflow and arterial pressure than conventional exercise (CE) when performed at the same relative heart rate (HR) intensity. Methods: 11 subjects (6M/5F) performed two 40-min treadmill exercise bouts at 65-70% of maximal HR. In the BFRE condition, cuffs around the upper thighs were inflated to 220 mmHg for 4 cycles of 5-min cuff inflation (occlusion)/5-min cuff deflation (reperfusion). The CE condition was identical, but without application of the cuffs. Mean arterial pressure (MAP), and plasma norepinephrine concentrations [NE] were compared between trials. Results: As hypothesized, BFRE resulted in higher [NE] compared to CE (923±92 vs 782±68 pg/ml; P=0.05). Unexpectedly, however, there were no differences in MAP between conditions during the cuff inflation time periods (BFRE vs. CE; P≥0.12)), and MAP was lower with BFRE during all 4 reperfusion periods compared to the CE trial (Cycle 1: BFRE vs. CE, 103±3 vs 107±2 mmHg; Cycle 2: 98±2 vs 103±2 mmHg; Cycle 3: 96±2 vs 102±2 mmHg; Cycle 4: 95±2 vs 100±2 mmHg; P≤0.04). Conclusion: BFRE elicited an exaggerated sympatho-excitatory response compared to CE as evidenced by higher plasma [NE]. This response was not accompanied by higher arterial pressures, however, most likely due to the cyclical nature of the occlusion/reperfusion protocol. The reactive hyperemia resulting from each cuff deflation may have offset the expected sympathetically-mediated increase in arterial pressure, resulting in an attenuation of the exercise pressor reflex. In conclusion, this novel cyclical BFRE paradigm could be applied to the clinical setting, such as cardiac or stroke-rehabilitation, where patients are already engaged in an exercise program, but where they could also benefit from the protection associated with RIPC.